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Immunology 8 - Autoimmunity (i) (Mechanisms of Autoimmunity (release of…
Immunology 8 - Autoimmunity (i)
tolerance
= failure of immune system to respond to antigen
self-tolerance NB
maintained by thymic education centrally
+ve selection in cortex
ensures all cells are protective (bind to MHC)
-ve selection in medulla
eliminated cells that are too strongly reactive (bind too strong to MHC)
if not autoimmune reactivity occurs
v common as self-tolerance isn't perfect
only becomes a disease (autoimmunity) if damage occurs
maintained by active regulation + absence of costim + danger signals peripherally
T cell activation requires 3 signals
1) antigen-specific signal (bound to MHC2 on DC) - recognised by TCR
2) co-stim signal - CD28 on T cell + CD80/86 (B7) on DC
often activated by infection
e.g. coxsackievirus (may lead to type 1 DM)
3) danger signal (cks)
if just signal 1, 2 outcomes...
apoptosis
irreversible
anergy (absence of the normal immune response)
reversible via IL2
for full activation + prolif
B cell tolerance
failure of T cell help
same for immature B cells in BM, and mature ones in periphery
deletion in response to multivalent (several attachment sites) self-antigen
anergy (or deletion if mature) in response to soluble self-antigen
Mechanisms of Autoimmunity
molecular mimicry
infection with organisms possessing antigens that are v similar to self antigens
cross-reactive Igs
superantigens
massive Th expansion that can't be controlled by Tregs
overwhelms regulatory mechanisms
activates large % of T cells
e.g. Kawasaki syndrome
tissue develops ability to express pathogen antigen
altered self
bypasses self-tolerance
drug hypersensitivity
may persist even when drug stopped
penicillin or hydralazine (antihypertensive - binds to self DNA + alters it)
release of sequestered antigen
not ordinarily available for recognition by immune system
not expressed in thymus
e.g. intraocular/testicular proteins
due to penetrating trauma/infection
good eye could get attacked
give short course low dose immunosuppressants
cryptic self epitopes
present @ v low conc, so don't delete auto reactive cells
no problem until defective epitope clearance occurs (buildup)
mutations in genes controlling immune responses
e.g. autoimmune lymphoproliferative syndrome (ALPS)
Fas/FasL mutations prevent lymphocyte death
immune response can't switch off - Lupus